Pharmacokinetics of SDZ RAD and cyclosporin including their metabolites in seven kidney graft patients after the rst dose of SDZ RAD
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1 Pharmacokinetics of SDZ RAD and cyclosporin including their metabolites in seven kidney graft patients after the rst dose of SDZ RAD Gabriele I. Kirchner, 1,4 Michael Winkler, 2 Lueke Mueller, 2 Christian Vidal, 1 Wolfgang Jacobsen, 1 Anke Franzke, 3 Siegfried Wagner, 4 Stefan Blick, 1 Michael P. Manns 4 & Karl-Friedrich Sewing 1 1 Institute for General Pharmacology, Medical School of Hannover, 2 Clinic of Abdominal and Transplant Surgery, Medical School of Hannover, 3 Department of Hematology and Oncology, Medical School of Hannover and 4 Department of Gastroenterology and Hepatology, Medical School of Hannover, Hannover, Germany Aims The aim of the study was to investigate the pharmacokinetics and metabolism of the new immunosuppressant SDZ RAD during concomitant therapy with cyclosporin in stable renal transplant patients. Furthermore, we studied the in uence of SDZ RAD on the pharmacokinetics of cyclosporin at steady state levels. Methods SDZ RAD was administered orally in different doses (.25±15 mg day x1 )to seven patients, who were on standard cyclosporin-based immunosuppression. The blood concentrations of both drugs including their main groups of metabolites were measured simultaneously by LC/electrospray-mass spectrometry. Results The mean area under the blood concentration-time curve to 12 h (AUC(,12 h)) was 4244t1311 mg l x1 h for cyclosporin before SDZ RAD treatment and 4683t1174 mg l x1 h(p=.16) on the day of SDZ RAD treatment (95% CI for difference -126, 13). On both study days C max, and t max of cyclosporin were not signi cantly different. The metabolite pattern of cyclosporin did not change. The pharmacokinetic data of SDZ RAD dose-normalized to 1 mg SDZ RAD were as follows: AUC(,24 h): 35.4t13.1 mg l x1 h, C max : 7.9t2.7 mg l x1 and t max : 1.5t.9 h. The metabolites of SDZ RAD found in blood were hydroxy-sdz RAD, dihydroxy-sdz RAD, demethyl-sdz RAD, and a ring-opened form of SDZ RAD. Conclusions A single dose of SDZ RAD did not in uence signi cantly the pharmacokinetics of cyclosporin. The most important metabolite of SDZ RAD was the hydroxy-sdz RAD, its AUC(,24 h) being nearly half that of the parent compound SDZ RAD. Keywords: cyclosporin, drug metabolism, electrospray-ms, metabolites, pharmacokinetics, SDZ RAD, therapeutic drug monitoring Introduction The new macrolide immunosuppressant SDZ RAD[4- O-(2-hydroxy)ethyl-rapamycin] has a molecular weight of dalton (C 53 H 83 NO 14 ) and is currently under clinical investigation in stable renal transplant recipients. SDZ RAD has a mode of action different from that of Correspondence: Dr Gabriele Kirchner, Institut fuèr Allgemeine Pharmakologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str.1, D-3625 Hannover, Germany. Tel.: / ; Fax: / ; Kirchner.Gabriele@MH-Hannover.DE Received 25 February 2, accepted 22 August 2. cyclosporin or tacrolimus. In contrast to the latter drugs, which inhibit the expression of T-cell growth factors such as IL-2 [1±3], SDZ RAD inhibits in general growth factor driven cell proliferation, including that of T-cells and vascular smooth muscle cells [4]. SDZ RAD and cyclosporin show greater than additive immunosuppression and the drugs are intended to be given in combination [5]. The advantage of SDZ RAD seems to be that it is less nephrotoxic [unpublished data from Novartis] than the standard immunosuppressants cyclosporin and tacrolimus which are associated with nephrotoxicity [6±9]. Cyclosporin, tacrolimus and sirolimus (rapamycin) are metabolized mainly by cytochrome P45 3A4 [1±13]. f 2 Blackwell Science Ltd Br J Clin Pharmacol, 5, 449±
2 Gabriele I. Kirchner et al. Therefore it may be predicted that SDZ RAD is metabolized by the same enzymes. In in vitro studies liver microsomes generated at least seven SDZ RAD metabolites and we could identify three SDZ RAD metabolites resulting from hydroxylation, demethylation and degradation [14]. The immunosuppressive activity of the SDZ RAD metabolites is unknown. Since h.p.l.c. with u.v. detection is not sensitive enough to assay concentrations lower than 2 mg l x1 in patients' blood, we had developed an LC/electrospray-mass spectrometric method for simultaneous measurement of SDZ RAD, cyclosporin and their metabolites [15]. It was the aim of the study using a speci c LC/ electrospray-mass spectrometric method to analyse the pharmacokinetics of SDZ RAD, cyclosporin and their metabolites after the rst oral SDZ RAD dose and to compare the pharmacokinetic data of cyclosporin under steady-state conditions and after a single dose of SDZ RAD. Methods Patients and blood sample collection Seven Caucasian stable kidney transplant recipients (1 female/6 male) under primary therapy with cyclosporin (administered every 12 h; trough levels between 8 and 15 mg l x1 ) and prednisone (dose <15 mg day x1 ) participated in a phase I study with SDZ RAD. These patients were part of an European multicentre study. The patients were instructed to take the drugs exactly at 8. h and 2. h 3 days before and during the study. Compliance was checked by a questionaire. In addition to their basic immunosuppression patients received between.25 mg day x1 and 15 mg day x1 of SDZ RAD for only one day in a single dose. SDZ RAD was administered as capsules. Patients were excluded who had to take other drugs known either to inhibit or induce cytochrome P45 3A [16] with the exceptions of methylprednisolone and prednisone. The mean age of the patients was 43 years (range 25±61 years). The patients had a mean weight of 78 kg (range 52±12 kg) and the mean time after transplantation was 6.6t4.2 years (range 1.25 years to 14.5 years). The study was approved by the local ethics committee, and all patients gave their written informed consent according to the revised Declaration of Helsinki. Blood samples were taken into EDTA containing tubes on the day before and on the day of SDZ RAD administration and were immediately frozen at x2uc until measurement. The samples were collected immediately before ( time) and.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 1, and 12 h after cyclosporin and SDZ RAD intake. In all patients clinical chemistry and haematological parameters on the day before SDZ RAD administration were measured. The mean value of gamma glutamyl transferase (c-gt) was slightly increased (mean = 27 U l x1 ; normal: up to 18 U l x1 ). All the other liver function tests [serum bilirubin, activities of alanine aminotransferase (ALAT), aspartate aminotransferase (ASAT), alkaline phosphatase (ALP), cholinesterase (CHE), glutamate dehydrogenase (GLDH)] were normal. Additionally glucose, cholesterol, triglycerides, leucocytes, haematocrit and thrombocytes were in normal ranges. The mean renal function tests were abnormal: serum creatinine averaged 125 mmol l x1 (normal 5±8 mmol l x1 ) and urea 1 mmol l x1 (normal 3.3±6.7 mmol l x1 ). The mean value of haemoglobin was decreased: 11.3 g dl x1 (normal 12±16 g dl x1 ). The serum parameters were measured daily using standard methods (Institut fuèr Klinische Chemie, Medizinische Hochschule Hannover, Hannover, Germany). Method of SDZ RAD, cyclosporin and their metabolites The h.p.l.c./electrospray-mass spectrometric technique used has been previously described [15]. Blood samples were deproteinized by methanol/.4 mol l x1 zinc sulphate solution (8 : 2, v/v). After centrifugation (49 rev min x1 for 6 min) supernatants were injected into the h.p.l.c. system (HP 19 series II liquid chromatograph; Hewlett-Packard, Waldbronn, Germany) and transferred to an extraction column (C-18 column). The compounds were enriched on the extraction column, while other compounds in the sample were transferred through the extraction column into the waste. Then the switching valve changed position and the extract was eluted in the back- ush mode and directly transferred onto the analytical column (25r2 mm Hypersil ODS column, particle size 5 mm). The compounds were separated on the analytical column under isocratic conditions (.2 ml min x1 of methanol/water 9/1; v/v) with a column temperature of 35uC, and were then injected into the electrospray-mass spectrometer. The h.p.l.c. system was linked to an API-electrospray cabinet HP59987A which was connected to an HP5989B mass spectrometer engine (Hewlett-Packard, Waldbronn, Germany). Data were recorded and analysed by HP LC/MS ChemStation consisting of the HP G134C MS ChemStation and the G147A LC/MS software (Hewlett Packard). The MS was run in the selected ion monitoring (SIM) mode and focused on the sodium adduct ions [M+Na] + of the following masses: atomic mass unit (amu) (demethyl-sdz RAD), 98.6 amu (SDZ RAD), amu (hydroxy-sdz RAD), amu (ring-opened form of SDZ RAD), amu (dihydroxy-sdz RAD), amu (cyclosporin), amu (hydroxy-cyclosporin) and amu (dihydroxy-cyclosporin). 45 f 2 Blackwell Science Ltd Br J Clin Pharmacol, 5, 449±454
3 Concentration of dihydroxy-cs (µg l 1 ) Concentration of hydroxy-cs (µg l 1 ) Concentration of cyclosporin (µg l 1 ) Pharmacokinetics of SDZ RAD and cyclosporin For quality control during the study two precision and calibration control samples each were run for every 1 study samples. The calibration curve in whole blood comprised nine data points at concentrations of /, 1/2, 3/6, 9/18, 15/3, 25/5, 35/7, 5/1, 75/ 15 mg l x1 with n=5 for each concentration of SDZ RAD/cyclosporin. The lower limit of quanti cation was.4 mg l x1 for SDZ RAD, cyclosporin and their metabolites. The calibration curves were linear from.4 to 1 mg l x1 for SDZ RAD (r 2 =.99) and 1±13 mg l x1 for cyclosporin (r 2 =.99). Recoveries of SDZ RAD and cyclosporin from blood were 96.t6% (mean t s.d.) and 94t5% (mean t s.d.), respectively. The interassay coef cients of variation were 9.2% at 3 mgl x1 and 8.8% at 5 mgl x1 for SDZ RAD and 9.8% at 6 mgl x1 and 9.6% at 7 mg l x1 for cyclosporin (n=15). Pharmacokinetic analysis Compartment-independent pharmacokinetic parameters of SDZ RAD, hydroxy-sdz RAD, dihydroxy-sdz RAD, ring-opened form of SDZ RAD, demethyl-sdz RAD, and of cyclosporin, hydroxy-cyclosporin, and dihydroxy-cyclosporin were evaluated using the TopFit version 2. software [17]. The maximal concentration (C max ), the corresponding time (t max ), the clearance and area under the curve (AUC(,12 h) or AUC(,24 h)) were determined. Since SDZ RAD exhibited dose proportional increases in C max and AUC (r 2 =.96 and r 2 =.92, respectively), the mean values of SDZ RAD including its metabolites were given in dose-normalized units. a b c Statistical analysis For statistical analysis Student's t-test for paired data was used to compare baseline with day 1 data. Differences between the pre and post-treatment values were given as means and 95% con dence intervals (CI). We used `SPSS for Windows 9.; SPSS Inc., Chicago, IL'; P-values of <.5 were considered signi cant. Figure 2 was designed with `GraphPad Prism, Version 2.' Figure 1 a) Mean (ts.d.) blood concentrations of cyclosporin, b) hydroxy-cyclosporin and c) dihydroxy-cyclosporin in seven stable kidney graft patients the day before (cyclosporin only, N) and on the day (cyclosporin and SDZ RAD, %) of SDZ RAD administration measured by LC/electrospray-mass spectrometry. Results Pharmacokinetics of cyclosporin and its metabolites in the steady-state All seven patients were treated orally with cyclosporin (baseline) so that cyclosporin trough levels were between 8 and 15 mg l x1. The pharmacokinetic pro les of cyclosporin and its metabolites of all patients are shown in Figure 1a±c. The main groups of cyclosporin metabolites were hydroxy-cyclosporin and dihydroxy-cyclosporin. During the rst 2.5 h the concentration of cyclosporin was higher than that of hydroxy-cyclosporin, but thereafter the concentration of hydroxy-cyclosporin increased while the concentration of cyclosporin rapidly decreased. The pharmacokinetic parameters (t max, C max, and AUC) of cyclosporin and its metabolites are shown in Table 1. During baseline therapy the mean AUC(,12 h) value was 4244t1311 mg l x1 h. Mean C max was 169t291 mg l x1 which was reached at a time of 1.3t.3 h. f 2 Blackwell Science Ltd Br J Clin Pharmacol, 5, 449±
4 Cyclosporin clearance (ml min 1 ) Gabriele I. Kirchner et al. Table 1 Pharmacokinetic parameters (mean t s.d.) of cyclosporin and its metabolites in the steady-state (baseline) and of cyclosporin and SDZ RAD including their metabolites during combination therapy (day 1). Based upon the assumption that there is a dose linearity the pharmacokinetic data of SDZ RAD including its metabolites were given as dose normalized values. The blood concentrations were measured by LC/electrospray-mass spectrometry. 3 2 C max (mg l x1 ) t max (h) In uence of a single dose of SDZ RAD on the pharmacokinetics of cyclosporin AUC(,12 h) (mg l x1 h) Baseline Cyclosporin 169t t t1311 Hydroxy-cyclosporin 638t79 2.2t.4 496t779 Dihydroxy-cyclosporin 16t14 3.4t.9 785t84 Day 1 Cyclosporin 1231t t t1174 Hydroxy-cyclosporin 737t t t923 Dihydroxy-cyclosporin 128t6 3.2t.6 997t22 AUC(,24 h) Day 1 (mg l x1 h) SDZ RAD 7.9t t t13.1 Hydroxy-SDZ RAD 2.8t t.9 16.t6.5 Dihydroxy-SDZ RAD 1.4t1. 1.6t.2 8.5t5.7 Demethyl-SDZ RAD 1.6t1.3 2.t1. 1.7t15.8 Ring-opened form of SDZ RAD.5t.4 1.2t.9 2.3t2.1 t max = time to maximal serum concentration, C max = maximum serum concentration, AUC = area under the concentration time curves. In addition to cyclosporin the patients received a single, oral dose of various concentrations of SDZ RAD (.25 mg to 15 mg) for 1 day (day 1). The concentration-time curves of the mean t s.d. concentrations of cyclosporin and its metabolites at baseline and day 1 are shown in Figure 1a,b,c. The pattern of the metabolites of cyclosporin did not change in the presence of SDZ RAD (Figure 1b,c). C max of cyclosporin amounted to 1231t345 mg l x1 at t max of 1.6t.6 h (Table 1). The mean AUC(,12 h) was 4683t1174 mg l x1 h. SDZ RAD, cyclosporin and most of the metabolites reached C max at about the same time (approximately 1.5 h). We could show that the mean C max values of baseline and day 1 (169 mg l x1 vs 1231 mg l x1 ) were not signi cantly different (mean difference 162 mg l x1 ; 95% CI x136±459 mg l x1 ; P=.233). The difference between the mean cyclosporin AUC(, 12 h) values alone and in the presence of SDZ RAD (4244 mg l x1 h vs 4683 mg l x1 h) did not reach signi cance (mean difference 439 mg l x1 h; 95% CI x126±13 mg l x1 ; P=.16). In the presence of SDZ RAD the metabolite pattern of cyclosporin did not show signi cant changes. The 1 AUC(,12 h) (mean difference 653 mg l x1 h; 95% con dence interval x189±1164 mg l x1 h; P=.123) and C max (mean difference 99 mg l x1 ; 95% CI x38±134 mg l x1 ; P=.6) of hydroxy-cyclosporin and AUC(,12 h) (mean difference 212 mg l x1 ; 95% CI x7.5±359 mg l x1 ; P=.57) and C max (mean difference 22 mg l x1 ; 95% CI x38±65 mg l x1 ; P=.528) of dihydroxy-cyclosporin did not change signi cantly in the presence of SDZ RAD. Cyclosporin clearance did not change signi cantly (P=.778) with increasing SDZ RAD doses (Figure 2). Pharmacokinetics of SDZ RAD and its metabolites after a single dose Four main types of metabolites: hydroxy-sdz RAD, dihydroxy-sdz RAD, demethyl-sdz RAD and a ringopened form of SDZ RAD were found in patients' blood (Figure 3). The pharmacokinetic data of SDZ RAD including its metabolites were given as dose-normalized to 1 mg. Hydroxy-SDZ RAD was the most important metabolite, its AUC(,24 h) was nearly half of that of the parent compound SDZ RAD (16.t6.5 mg l x1 h vs 35.4t13.1 mg l x1 h). Pharmacokinetic data including that of the other SDZ RAD metabolites are shown in Table 1. SDZ RAD reached after 1.5t.9 h (t max ) the C max of 7.9t2.7 mg l x1. C max of hydroxy-sdz RAD was 2.8t2.8 mg l x1 and appeared after 1.7t.9 h. Discussion y=.65x±144 r 2 = SDZ-RAD (µg l 1 ) Figure 2 Cyclosporin clearance as a function of SDZ RAD dose in seven patients. The regression line and a con dence interval for the regression slope as shown. CSA = cyclosporin. This report has shown that in stable renal transplant recipients SDZ RAD is metabolized and that a single dose of SDZ RAD does not affect the pharmacokinetics of cyclosporin. The main metabolite of SDZ RAD appearing in blood is a monohydroxylated form. Dihydroxy and 452 f 2 Blackwell Science Ltd Br J Clin Pharmacol, 5, 449±454
5 Dose-normalized concentrations (µg l 1 ) Pharmacokinetics of SDZ RAD and cyclosporin one of the main metabolites has immunosuppressive or toxic effects. Additionally, the pharmacokinetics of cyclosporin and its metabolites were not signi cantly in uenced by a single dose of SDZ RAD. We thank Renate Schottmann, Ingelore Hackbarth, and Annette Linck for their technical assistance. This work was supported by a grant of the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 265 A Figure 3 Mean dose normalized blood concentrations of SDZ RAD and its metabolites (N SDZ RAD, % hydroxy SDZ RAD, dihydroxy SDZ RAD, x ring opened SDZ RAD, * demethyl SDZ RAD) in seven stable kidney graft patients on the day of SDZ RAD administration measured by LC/ESI-MS. demethyl SDZ RAD and a ring-opened form were detectable in much lower concentrations. At least the rst three metabolites suggest that the cytochrome P45 system is involved. In analogy to what is known from related compounds such as tacrolimus and sirolimus [1±13] it can be hypothesized that the subfamily CYP 3A plays a major role in the metabolism of SDZ RAD. This in turn would raise the concern that there might be pharmacokinetic interactions between SDZ RAD and other drugs metabolized by CYP 3A, e.g. cyclosporin. Our pharmacokinetic data of cyclosporin before administration of SDZ RAD are in good agreement with the previously published data [18±2]. The present investigation excluded a signi cant in uence of SDZ RAD in a single dose either on the time-concentration relationship or the metabolism of cyclosporin under steady state conditions. Further studies are needed to investigate the interactions of SDZ RAD and cyclosporin under longterm administration. Irrespective of SDZ RAD dosage all patients had the same metabolite pattern (data not shown). Compared with blood concentrations of cyclosporin metabolites, which reached higher trough values than the parent compound [21], the SDZ RAD metabolite fraction in blood was relatively small. Nevertheless there is need to investigate the properties of the metabolites in further studies. In our study we presented pharmacokinetic data and the metabolite pattern of SDZ RAD after oral intake in humans. SDZ RAD is metabolized to at least four types of metabolites. We showed that hydroxy-sdz RAD is the main metabolite of SDZ RAD with an AUC(,24 h) nearly half of that of the parent compound. Therefore it is important to investigate whether hydroxy-sdz RAD or References 1 KroÈnke M, Leonard WJ, Depper JM, Arya SK, Wong Staal F, Gallo RC. Cyclosporin A inhibits T-cell growth factor gene expression at the level of mrna transcription. Proc Natl Acad Sci USA 1984; 81: 5214± Bierer BE, HollaÈnder G, Frumann D, Burakoff SJ. Cyclosporin A and FK56: molecular mechanisms of immunosuppression and probes and transplantation biology. Curr Opin Immunol 1993; 5: 763± Emmel EA, Verweij CL, Durand DB, Higgins KM, Lacy E, Crabtree GR. Cyclosporin A speci cally inhibits function of nuclear proteins involved in T cell activation. Science 1989; 246: 1617± Schuler W, Sedrani R, Cottens S, et al. SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation 1997; 64: 36±42. 5 Schuurman H-J, Cottens S, Fuchs S, et al. SDZ RAD, a new rapamycin derivative. Transplantation 1997; 64: 32±35. 6 Neuhaus P, McMaster P, Calne R, et al. Neurological complications in the European multicentre study of FK56 and cyclosporin in primary liver transplantation. Transplant Int 1994; 7(Suppl 1): 27±31. 7 Schachter M. Cyclosporine A and hypertension. J Hypertension 1988; 6: 511± Devlin J, Williams R, Neuhaus P, et al. Renal complications and development of hypertension in the European study of FK56 and cyclosporin in primary liver transplant recipients. Transplant Int 1994; 7(Suppl 1): 22±24. 9 Alessiani M, Cillo U, Fung J, et al. Adverse effects of FK56 overdosage after liver transplantation. Transplant Proc 1993; 25: 628± Kahan BD. Cyclosporine. N Engl J Med 1989; 321: 1725± Lorber MI. Cyclosporine: lessons learned ± future strategies. Clin Transplant 1991; 5: 55± Vincent SH, Karaman B, Painter S, et al. In vitro metabolism of FK56 in rat, rabbit, and human liver microsomes: identi cation of a major metabolite and of cytochrome P-45 3A as the major enzymes responsible for its metabolism. Arch Biochem Biophys 1992; 294: 454± Sattler M, Guengerich FP, Yun CH, Christians U, Sewing K-Fr. Cytochrome P45 3A, enzymes are responsible for biotransformation of FK. 56 and rapamycin in man and rat. Drug Metab Dispos 1992; 2: 753± Vidal C, Kirchner GI, Sewing K-Fr. Structural elucidation by electrospray mass spectrometry ± an approach to the in vitro metabolism of the macrolide immunosuppressant SDZ RAD. J Am Soc Mass Spectrom 1998; 9: 1267± Kirchner GI, Vidal C, Winkler M, et al. LC/ESI-MS allows simultaneous and speci c quanti cation of SDZ RAD and f 2 Blackwell Science Ltd Br J Clin Pharmacol, 5, 449±
6 Gabriele I. Kirchner et al. ciclosporin including their metabolites in human blood. Ther Drug Monit. 1999; 21: 116± Pichard L, Fabre JM, Domergue J, et al. Molecular mechanism of cyclosporine A drug interactions: inducers and inhibitors of cytochrome P45 screening in primary cultures of human hepatocytes. Transplant Proc 1991; 23: 978± Heinzel G, Woloszczak R, Thomann P. TopFit, Version 2., Pharmacokinetic and Pharmacodynamic Data Analysis System for the PC. Dr. Karl Thomae: Stuttgart; G. Fischer: New York., Fahr A. Cyclosporin clinical pharmacokinetics. Clin Pharmacokin 1993; 24: 472± Mueller EA, Kovarik JM, van Bree JB, Lison AE, Kutz K. Pharmacokinetics and tolerability of a microemulsion formulation of cyclosporine in renal allograft recipients ± a concentration-controlled comparison with the commercial formulation. Transplantation 1994; 57: 1178± Kovarik JM, Mueller EA, van Bree JB, et al. Cyclosporine pharmacokinetics and variability from a microemulsion formulation ± a multicenter investigation in kidney transplant patients. Transplantation 1994; 58: 658± Christians U, Sewing K-Fr. Cyclosporine metabolism in transplant patients. Pharmac Ther 1993; 57: 291± f 2 Blackwell Science Ltd Br J Clin Pharmacol, 5, 449±454
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